ES2267695T3 - PHARMACETUTICS PREPARATIONS CONTAINING EXTRACTS OF ISOFLAVONA SOYA AND PROBIOTIC MICROORGANISMS. - Google Patents
PHARMACETUTICS PREPARATIONS CONTAINING EXTRACTS OF ISOFLAVONA SOYA AND PROBIOTIC MICROORGANISMS. Download PDFInfo
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- ES2267695T3 ES2267695T3 ES01402270T ES01402270T ES2267695T3 ES 2267695 T3 ES2267695 T3 ES 2267695T3 ES 01402270 T ES01402270 T ES 01402270T ES 01402270 T ES01402270 T ES 01402270T ES 2267695 T3 ES2267695 T3 ES 2267695T3
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- Prior art keywords
- isoflavones
- lactobacillus
- probiotic microorganisms
- microorganisms
- use according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- UQZIYBXSHAGNOE-XNSRJBNMSA-N stachyose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)O2)O)O1 UQZIYBXSHAGNOE-XNSRJBNMSA-N 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 208000014794 superficial urinary bladder carcinoma Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000013548 tempeh Nutrition 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- YWYZEGXAUVWDED-UHFFFAOYSA-N triammonium citrate Chemical compound [NH4+].[NH4+].[NH4+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YWYZEGXAUVWDED-UHFFFAOYSA-N 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
Abstract
Utilización de una preparación farmacéutica que comprende unos extractos titulados en isoflavonas de soja y unos microorganismos probióticos vivos, como producto de combinación para una administración simultánea, separada o extendida en el tiempo para la preparación de un medicamento, útil en el tratamiento de los sofocos asociados a la menopausia, caracterizada porque los microorganismos probióticos son escogidos en el grupo constituido por Enterococcus faecium, Propionibacterium acidipropionici, Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus rhamnosus, Pediococcus acidilactici y Streptococcus thermophilus y las mezclas de estos microorganismos.Use of a pharmaceutical preparation comprising extracts titled in soy isoflavones and live probiotic microorganisms, as a combination product for simultaneous administration, separated or extended in time for the preparation of a drug, useful in the treatment of associated hot flashes at menopause, characterized in that the probiotic microorganisms are chosen from the group consisting of Enterococcus faecium, Propionibacterium acidipropionici, Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus rhamnosuscususcususcususcususcususcususcuscuscusususcuscuscususcuscuscususcuscuscuscususcuscuscususcuscuscuscususcuscuscususcuscuscususus.us
Description
Preparaciones farmacéuticas que contienen extractos de isoflavona de soja y microorganismos probióticos.Pharmaceutical preparations containing Soy isoflavone extracts and probiotic microorganisms.
La presente invención se refiere a unas asociaciones entre unas isoflavonas de soja y unos microorganismos probióticos y a su aplicación en terapéutica.The present invention relates to associations between soy isoflavones and microorganisms probiotics and their application in therapeutics.
La soja pertenece a la familia de las Fabaceae. El fruto de la soja es una vaina que contiene unos granos redondeados u ovoides encerrados de dos en dos, tres, o cuatro. Estos granos de soja están compuestos esencialmente por glúcidos, proteínas y lípidos. Los glúcidos, que representan 16 a 25% de la materia, están constituidos por azúcares simples como la sacarosa, la rafinosa y la estaquiosa, las pentosamas y las galactosanas, pero muy poco almidón. Las proteínas son abundantes puesto que representan 35 a 40% de la materia y están constituidas principalmente por albúminas y globulinas. Es esta riqueza en proteínas la que da el valor alimenticio a los granos de soja. Los lípidos corresponden a 15 a 20% de la materia y están constituidos principalmente por glicéridos de ácidos grasos saturados o insaturados, por un insaponificable rico en fitoesteroles y por una fracción lipídica polar rica en fosfolípidos llamada lecitina.Soy belongs to the Fabaceae family . The fruit of the soybean is a pod that contains rounded grains or ovoids enclosed in two, two, three, or four. These soybeans are essentially composed of carbohydrates, proteins and lipids. The carbohydrates, which represent 16 to 25% of the matter, are constituted by simple sugars such as sucrose, raffinose and stachyose, pentosamas and galactosanas, but very little starch. Proteins are abundant since they represent 35 to 40% of the matter and consist mainly of albumin and globulins. It is this richness in protein that gives the nutritional value to soybeans. Lipids correspond to 15 to 20% of the matter and consist mainly of glycerides of saturated or unsaturated fatty acids, an unsaponifiable rich in phytosterols and a phospholipid-rich polar lipid fraction called lecithin.
Las isoflavonas son también un elemento constitutivo importante de los granos de soja, pero el contenido de isoflavonas de la soja es considerablemente variable en función de la especie, la madurez de la planta y de las condiciones de cultivo. Estas isoflavonas son unos polifenoles heterocíclicos que se caracterizan por un encadenamiento en C15 del tipo Ar-C_{3}-Ar dispuestos según el motivo 1,2-difenilpropánico. La estructura general viene dada en la fórmula (1) siguiente:Isoflavones are also an element important constituent of soybeans, but the content of Soy isoflavones is considerably variable depending on the species, the maturity of the plant and the growing conditions. These isoflavones are heterocyclic polyphenols that are characterized by a chain in C15 of the type Ar-C_ {3} -Ar arranged according to 1,2-diphenylprophanic motif. General structure It is given in the following formula (1):
En la planta, las principales isoflavonas, la genisteina de fórmula (2)In the plant, the main isoflavones, the genistein of formula (2)
y la daidzeina de fórmula (3) en la que R_{7}=hidrógenoand the daidzein of formula (3) in the that R 7 = hydrogen
están presentes en formas diferentes: glicósidos, malónidos, acetilos y agliconos, siendo esta última una forma minoritaria puesto que no representa más de 1 a 2% de las isoflavonas totales. Las conjugaciones se producen en la posición 7.are present in forms different: glycosides, malonides, acetyls and aglycone, this being last a minority form since it does not represent more than 1 to 2% of the total isoflavones. Conjugations occur in the position 7.
Wang H. et al. (j. Agric Food Chem. (1994) 42, nº 8, páginas 1666 a 1673) han determinado la presencia de 2, 275 mg de isoflavonas, por gramo de soja, en todas las formas citadas anteriormente, lo que corresponde a unos contenidos del 43% de daidzeina y 57% de genisteina.Wang H. et al. ( j. Agric Food Chem. (1994) 42, No. 8, pages 1666 to 1673) have determined the presence of 2,275 mg of isoflavones, per gram of soybeans, in all the forms mentioned above, which corresponds to some contents 43% of daidzein and 57% of genistein.
Tham D.M. et al. (J. Clin Endocrinol. Metab. (1998) 83, nº 7, páginas 2232 a 2235) han titulado dos especies diferentes con 1,005 mg/g y 4,031 mg/g con 36% y 32% respectivamente de daidzeina.Tham DM et al. ( J. Clin Endocrinol. Metab. (1998) 83, No. 7, pages 2232 to 2235) have titled two different species with 1,005 mg / g and 4,031 mg / g with 36% and 32% respectively of daidzein.
Patent abstract of Japan, vol. 1998 nº 1, 30 enero 1998, \NAK JP 09238647 menciona un alimento susceptible de prevenir el cáncer y que contiene unas isoflavonas obtenidas por hidrólisis de las isoflavonas glicósidos contenidas en la leche de soja mediante la acción de microorganismos sobre dicha leche de soja, perteneciendo dichos microorganismos al género Lactobacilus, Bifidobacterium, Streptococus, Bacillus, Sacharomyces, Torulaspora y Cándida.Patent abstract of Japan, vol. 1998 nº 1, January 30, 1998, \ NAK JP 09238647 mentions a food susceptible to preventing cancer and containing isoflavones obtained by hydrolysis of the isoflavones glycosides contained in soy milk by means of the action of microorganisms on said soy milk, belonging said microorganisms to the genus Lactobacilus, Bifidobacterium, Streptococus, Bacillus, Sacharomyces, Torulaspora and Candida.
La solicitud internacional WO 00/03684 describe unas formulaciones a base de soja cuya concentración de isoflavonas es superior a las contenidas en el producto natural. Estas formulaciones pueden eventualmente comprender un medicamento como por ejemplo unos tratamientos hormonales de sustitución, así como otros elementos diferentes como por ejemplo unas enzimas de la digestión o unas vitaminas, pero nunca se hace mención de los microorganismos.International application WO 00/03684 describes some formulations based on soybean whose concentration of isoflavones It is superior to those contained in the natural product. These formulations may eventually comprise a medication such as for example hormone replacement treatments, as well as other different elements such as enzymes of the digestion or some vitamins, but there is never mention of microorganisms
Estas composiciones disminuyen los efectos de la menopausia, en particular los sofocos (página 18 líneas 16 a 17 + página 19 línea 11 a página 20 línea 12).These compositions diminish the effects of menopause, particularly hot flashes (page 18 lines 16 to 17 + page 19 line 11 to page 20 line 12).
La solicitud de patente internacional WO 99/07239 describe una combinación de fructooligosacarido, harina de soja que contiene unos flavonoides y granos de lino triturados que contienen unos lignanos, aptos para aumentar la actividad intestinal y facilitar la conversión de los fitoestrógenos en unas formas utilizables por los intestinos, así como su absorción. En esta combinación, los fructooligosacáridos son utilizados por sus efectos probióticos, es decir por su capacidad de aumentar de manera selectiva el crecimiento de las bifidobactérias y de los lactobacilos que aumentan la producción de ácidos en los intestinos. Estas composiciones son útiles para tratar los síntomas de la menopausia.WO international patent application 99/07239 describes a combination of fructooligosaccharide, flour soybeans containing flavonoids and crushed flax grains that contain some lignans, suitable for increasing intestinal activity and facilitate the conversion of phytoestrogens in some ways Usable by the intestines, as well as their absorption. In this combination, fructooligosaccharides are used for their effects probiotics, that is to say for its ability to increase so selective growth of bifidobacteria and lactobacilli that increase the production of acids in the intestines. These compositions are useful for treating the symptoms of menopause.
La solicitud internacional WO 98/21945 describe unas composiciones que son susceptibles de disminuir las manifestaciones del SPRT, (Symptoms of Persistent Reproductive Transition), entre las cuales los sofocos, estas composiciones contienen unos fitoestrógenos, en particular fruto de la asociación entre la soja con unos azúcares y unas colinas.International application WO 98/21945 describes compositions that are likely to decrease SPRT manifestations, (Symptoms of Persistent Reproductive Transition), among which hot flashes, these compositions they contain phytoestrogens, in particular the result of the association between soybeans with sugars and hills.
De hecho, de manera general, se considera el valor de 2 mg de isoflavona por gramo de soja en el grano seco.In fact, in general, the 2 mg isoflavone value per gram of soybeans in the dry grain.
La estructura de las isoflavonas presenta unas homologías con las de los estrógenos. Así, sin ser esteroides, la genisteina y la daidzeina poseen unos grupos hidroxilos en la posición 7 y 4’ en una configuración estereoquímica análoga a la de los hidroxilos de la molécula de estradiol de fórmula (4).The structure of isoflavones has some homologies with those of estrogens. So, without being steroids, the genistein and daidzein have hydroxyl groups in the position 7 and 4 ’in a stereochemical configuration analogous to that of hydroxyls of the estradiol molecule of formula (4).
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Debido a esta homología estructural con el estradiol, y más particularmente debido a la distancia y al ángulo diedro entre los dos grupos hidroxilos, las isoflavonas tienen una actividad estrogénica. Pueden, en efecto enlazarse como el estradiol sobre los receptores del tipo II (\beta) (Benneteau-Pelissero, Carta Científica del Instituto francés para la nutrición (1997) 47), de todas formas esta actividad es al menos 500 veces más débil que la del estradiol.Due to this structural homology with the estradiol, and more particularly due to distance and angle dihedral between the two hydroxyl groups, isoflavones have a estrogenic activity They can, in effect, bind like estradiol over type II receptors (β) (Benneteau-Pelissero, Scientific Letter of the Institute French for nutrition (1997) 47), however this activity It is at least 500 times weaker than that of estradiol.
En efecto, si se fija a 100 la actividad del estradiol, entonces la daidzeina tiene una actividad de 0,013, la genisteina una actividad de 0,084 y el ecuol, derivado metabólico de la daidzeina, tiene una actividad de 0,61 (Markiewicz L., J. Steroid Biochem. Molec. Biol. (1993), 45, páginas 399 a 405).Indeed, if the activity of estradiol is set at 100, then daidzein has an activity of 0.013, genistein has an activity of 0.084 and the equol, metabolic derivative of daidzein, has an activity of 0.61 (Markiewicz L., J. Steroid Biochem. Molec. Biol. (1993), 45, pages 399 to 405).
La soja es consumida por las poblaciones asiáticas, más particularmente en sus formas fermentadas como el miso o el tempeh. La observación de estas poblaciones, que tienen por lo tanto una alimentación muy rica en fitoestrógenos y consumen entre 20 y 150 mg de isoflavonas al día, MurkiesA. et al. (J. Clin. Endocrinol. Metab. (1998) 83, nº 2, páginas 297 a 303), ha revelado unas diferencias con respecto a las poblaciones occidentales en el plano de la salud. Estas poblaciones presentan:Soy is consumed by Asian populations, more particularly in its fermented forms such as miso or tempeh. The observation of these populations, which therefore have a diet very rich in phytoestrogens and consume between 20 and 150 mg of isoflavones a day, MurkiesA. et al . ( J. Clin. Endocrinol. Metab . (1998) 83, No. 2, pages 297 to 303), has revealed differences with respect to western populations in the health field. These populations present:
- --
- 4 a 10 veces menos posibilidades de morir de un cáncer hormonodependiente (seno, endometrio, próstata y colon), 4 10 times less chance of dying from cancer hormone dependent (breast, endometrium, prostate and colon),
- --
- menos síntomas relacionados con los desórdenes hormonales cuando se produce la menopausia (osteoporosis, sofocos), y fewer symptoms related to hormonal disorders when produces menopause (osteoporosis, hot flashes), and
- --
- menos enfermedades coronarias y del corazón. less coronary heart disease
Debido a su homología estructural con los
estrógenos, las isoflavonas son a menudo utilizadas en medicina,
principalmente en ginecología medica. Así Wilcox et al.
(BMJ (1990) 24, páginas 1757 a 1761) y Washburn S.A: et
al. (Third Internacional conference on
phyto-oestrogens (1995) Little Rock, USA) han
demostrado respectivamente, en unos estudios controlados contra
placebo, un descenso importante y significativo de los sofocos
durante la ingestión de soja a razón de 40 g/día durante 6 semanas.
Albertazzi P. et al. (Am. J. Obstet. Gynecol. (1998) 91,
páginas 6 a 11) han confirmado este efecto con 60 g de soja (es
decir 75 mg de isoflavonas) por día en un estudio randomizado en más
de 100 mujeres menopáusicas. Estos estudios demuestran
consecuentemente el efecto fitoestrógeno sobre los
sofocos.Due to their structural homology with estrogens, isoflavones are often used in medicine, mainly in medical gynecology. Thus Wilcox et al. ( BMJ (1990) 24, pages 1757 to 1761) and Washburn SA: et al. (Third International conference on phyto-oestrogens (1995) Little Rock, USA) have shown respectively, in placebo-controlled studies, a significant and significant decrease in hot flashes during soybean intake at a rate of 40 g / day for 6 weeks . Albertazzi P. et al. (Am. J. Obstet. Gynecol. (1998) 91, pages 6 to 11) have confirmed this effect with 60 g of soy (i.e. 75 mg of isoflavones) per day in a randomized study in more than 100 menopausal women. These studies consistently demonstrate the phytoestrogen effect on
hot flushes.
Además, Valente M. et al. (Calcif Tissue int. (1994), 54 páginas 377 a 380) ha realizado, en la mujer, unos estudios con la ipriflavona, prodroga sintética de la daidzeina, a razón de 500 a 600 mg al día y ha mostrado en 40 mujeres menopáusicas que sufren osteoporosis, una ganancia ósea a nivel de L1-L5 con un retorno a la normalidad en 12 meses. Gambacciani M. et al. (Bone and mineral, 26, páginas 19 a 25) ha demostrado que se pueden también evitar las pérdidas óseas en las mujeres subagonistas del LHRH (Luteinizing Hormone Refeasing Hormona). Blair et al. (J. Cell. Biochem., 1996, 61, páginas 629 a 637) explican esta acción poniendo en evidencia una inhibición de la actividad osteoclástica por la genisteina.In addition, Valente M. et al . (Calcif Tissue int. (1994), 54 pages 377 to 380) has conducted, in women, studies with ipriflavone, a synthetic prodrug of daidzein, at a rate of 500 to 600 mg per day and has shown in 40 menopausal women suffering from osteoporosis, a bone gain at the level of L1-L5 with a return to normal within 12 months. Gambacciani M. et al . (Bone and mineral, 26, pages 19 to 25) have shown that bone loss can also be avoided in subagonist women of LHRH (Luteinizing Hormone Refeasing Hormone). Blair et al . (J. Cell. Biochem., 1996, 61, pages 629 to 637) explain this action by demonstrating an inhibition of osteoclast activity by genistein.
En el caso de los cánceres hormonales dependientes, Barnes S. et al. (Diet and cancer: markers, prevention and treatment (1994) Plenum Press, páginas 135 a 147) han demostrado una reducción del número y el tamaño de los tumores. Unos estudios fundamentales realizados por Pagliacci N.C. et al. (European J. of Cancer (1994) 30 A (11), páginas 1675 a 1682) han demostrado la inhibición de las células cancerosas mamarias humanas por los fitoestrógenos, mientras que Wutke W. (in Proceedings of 2º Congreso de la sociedad europea de ginecología (1997)) ha evidenciado la inhibición de la expresión de los genes responsables del crecimiento de cultivos celulares. Finalmente, el estudio de Lee H.P. et al. (Lancet (1991)337, nº 18, páginas 1197 a 1200) ha demostrado que el riesgo de cáncer de mama baja con una alimentación rica en soja en la mujer menopáusica.In the case of hormone dependent cancers, Barnes S. et al . ( Diet and cancer: markers, prevention and treatment (1994) Plenum Press, pages 135 to 147) have shown a reduction in the number and size of tumors. Fundamental studies conducted by Pagliacci NC et al . ( European J. of Cancer (1994) 30 A (11), pages 1675 to 1682 ) have demonstrated the inhibition of human breast cancer cells by phytoestrogens, while Wutke W. ( in Proceedings of 2nd Congress of the European Society of Gynecology (1997)) has shown the inhibition of the expression of the genes responsible for the growth of cell cultures. Finally, the study by Lee HP et al . ( Lancet (1991) 337, No. 18, pages 1197 to 1200) has shown that the risk of breast cancer decreases with a diet rich in soybeans in menopausal women.
El intestino delgado es el lugar privilegiado
para la absorción de las isoflavonas puesto que la superficie de
contacto es grande, y el riego sanguíneo denso. De todas formas,
únicamente las formas agliconos (genisteina y daidzeina) son
absorbidas puesto que los glicósidos tienen una hidrofilia demasiado
grande, y un peso molecular demasiado
grande.The small intestine is the privileged place for the absorption of isoflavones since the contact surface is large, and the blood supply is dense. However, only the aglycone forms (genistein and daidzein) are absorbed since the glycosides have a hydrophilicity that is too large, and a molecular weight that is too high.
big.
Se ha demostrado que sólo las formas agliconos tienen una actividad estrogénica en los animales (Tham D.M. et al. ya citado y Moreau L. et al. (Referencias en ginecología obstétrica (1999) páginas 229 a 234, Springer-Verlag). La biotransformación de las isoflavonas glicosiladas en ecuol, genisteina y daidzeina es por lo tanto necesaria para la observación de los efectos benéficos de la soja.It has been shown that only aglycone forms have an estrogenic activity in animals (Tham DM et al . Already cited and Moreau L. et al . ( References in obstetric gynecology (1999) pages 229-234, Springer-Verlag). Biotransformation. of the glycosylated isoflavones in ecuol, genistein and daidzein is therefore necessary for the observation of the beneficial effects of soy.
Chang Y.C. et al. (J. Nat. Prod. (1995) 58, nº 12, páginas 1892 a 1896) han demostrado que esta transformación necesaria de las isoflavonas glicosiladas (daidzina y genistina) en daidzeina y genisteina y ecuol es realizada por la microflora intestinal.Chang YC et al . ( J. Nat. Prod. (1995) 58, No. 12, pages 1892 to 1896) have shown that this necessary transformation of glycosylated isoflavones (daidzine and genistin) into daidzein and genistein and ecuol is performed by intestinal microflora.
Para utilizar las isoflavonas, la flora intestinal comprende por lo tanto unas bacterias capaces de hidrolizar los enlaces B 1-4 y liberar así las formas agliconos. Estos microorganismos secretan unas enzimas tales como unas \beta-glucufunidasa, pero esta desglicosilación es también realizada en parte por simple hidrólisis gracias al ácido clorhídrico gástrico.To use isoflavones, the flora intestinal therefore comprises bacteria capable of hydrolyze bonds B 1-4 and thus release Aglycone shapes. These microorganisms secrete enzymes such like? -glucufunidase, but this deglycosylation is also performed in part by simple hydrolysis thanks to gastric hydrochloric acid.
Finalmente, las moléculas ya absorbidas, y por lo tanto conjugadas, pueden ser desconjugadas y reabsorbidas gracias a las enzimas \beta-glucoronidasa y arilsulfurasa.Finally, the molecules already absorbed, and by therefore conjugated, they can be deconjugated and reabsorbed thanks to the enzymes? -glucoronidase and arylsulfurase
La diversidad de la microflora intestinal realiza una función importante en las vías de metabolización y la biodisposnibilidad de las isoflavonas, en particular los Lactobacilos, los Bacteroides y las Bifidobacterias (Xu X. et al. (1995) Bioavallability of soybean isoflavons depends upon gut microflora in women I, Nutro 125, páginas 2307 a 2315).The diversity of the intestinal microflora plays an important role in the metabolic pathways and the bioavailability of isoflavones, particularly Lactobacilli , Bacteroides and Bifidobacteria (Xu X. et al . ( 1995 ) Bioavallability of soybean isoflavons depends upon gut microflora in women I , Nutro 125, pages 2307 to 2315).
\newpage\ newpage
En general la conversión es eficaz, y únicamente 14 a 43% de las isoflavonas ingeridas son encontradas de nuevo intactas en la orina.In general the conversion is effective, and only 14 to 43% of ingested isoflavones are found again intact in the urine
De todas formas, existe una gran variedad
metabólica individual y Moreau et al. (Referencias en
ginecología obstétrica ya mencionado) han demostrado que 30% de
la población no tiene una flora capaz de metabolizar el ecuol- la
forma aglicono más eficaz con respecto a los efectos estrogénico -
lo que hace difícil un tratamiento con
isoflavonas.However, there is a large individual metabolic variety and Moreau et al . ( References in obstetric gynecology already mentioned ) have shown that 30% of the population does not have a flora capable of metabolizing the equol- the most effective aglycone form with respect to estrogenic effects - which makes treatment with
isoflavones
Los probióticos son "unos organismos vivos que, ingeridos en cantidad suficiente, ejercen unos efectos beneficiosos en la salud que van más allá de las virtudes nutricionales que les son inherentes". Los beneficios en la salud no se limitan a la mejora del equilibrio microbiano a nivel del intestino, sino que pueden recubrir otros efectos. Así, para las bacterias lácticas, se han observado cinco tipos de efectos:Probiotics are "living organisms that, ingested in sufficient quantity, exert some effects beneficial in health that go beyond the virtues nutritional factors that are inherent to them. "The health benefits they are not limited to the improvement of microbial balance at the level of intestine, but may cover other effects. So, for lactic bacteria, five types of effects have been observed:
- --
- Efectos sobre el tubo digestivo: mejora de la digestión de la lactosa en las personas deficientes en lactasa, prevención de los desórdenes intestinales, adherencia a los cultivos de células intestinales, estimulación de la inmunidad intestinal en los modelos animales, estabilización de la enfermedad de Crohn y regularización de la motilidad intestinal.Effects on the digestive tract: improvement of lactose digestion in people deficient in Lactase, prevention of intestinal disorders, adherence to intestinal cell cultures, stimulation of immunity intestinal in animal models, disease stabilization of Crohn and regularization of intestinal motility.
- --
- Modificación de la microflora: equilibrio de las bacterias intestinales, aumento de las bacterias fecales, disminución de la actividad de las enzimas fecales, disminución de la mutagenicidad fecal, alivio de los síntomas de la intolerancia a la lactosa y colonización del tubo digestivo.Modification of the microflora: balance of intestinal bacteria, increase of bacteria fecal, decreased activity of fecal enzymes, decreased fecal mutagenicity, relief of symptoms of lactose intolerance and tube colonization digestive.
- --
- Efecto sobre la diarrea: prevención y/o tratamiento de las diarreas agudas y con rotavirus, reducción de las diarreas con rotavirus, prevención de la diarrea asociada a los antibióticos, tratamiento de las diarreas recidivantes con Clostridium difícil y tratamiento de las diarreas persistentes en el niño.Effect on diarrhea: prevention and / or treatment of acute and rotavirus diarrhea, reduction of diarrhea with rotavirus, prevention of diarrhea associated with antibiotics, treatment of recurrent diarrhea with difficult Clostridium and treatment of persistent diarrhea in the boy.
- --
- Efectos sistémicos: estimulación de la actividad fagocitaria, estimulación de la producción del interferón \gamma por los cultivos de células mononucleares de la sangre humana, reducción de la hipertensión en los modelos animales y humanos, efectos beneficiosos en el cáncer superficial de vejiga y alivio de los síntomas clínicos en los niños afectados de dermatitis óptica.Systemic effects: stimulation of phagocytic activity, stimulation of interferon production γ by blood mononuclear cell cultures human, reduction of hypertension in animal models and human, beneficial effects on superficial bladder cancer and Relief of clinical symptoms in children affected by dermatitis optics.
- --
- Efectos fisiológicos: producción de bacteriocinas y efecto antagonista contra el Helicobacter pylori.Physiological effects: production of bacteriocins and antagonistic effect against Helicobacter pylori .
En cuanto a las Bifidobacterias, éstas mejoran el transito gastrointestinal, disminuyen el riesgo de cáncer de colon y poseen una actividad antimicrobiana y efectos inmunorreguladores, mientras que el Lactobacillus acidophilus posee efectos hipocolesterolemizante, antimicrobiano e inmunorregulador y previene al cáncer de colon.As for Bifidobacteria, these improve gastrointestinal transit, decrease the risk of colon cancer and have an antimicrobial activity and immunoregulatory effects, while Lactobacillus acidophilus has hypocholesterolemic, antimicrobial and immunoregulatory effects and prevents colon cancer.
Por lo tanto, parece necesario paliar la baja actividad estrogénica de las isoflavonas y mejorar su actividad en los pacientes que presentan unos síntomas pre y/o menopáusicos y más particularmente en los pacientes que presentan poca o ninguna respuesta.Therefore, it seems necessary to alleviate the decline estrogenic activity of isoflavones and improve their activity in patients who have pre and / or menopausal symptoms and more particularly in patients who have little or no reply.
Ahora bien, los inventores han encontrado de manera sorprendente que ciertos microorganismos probióticos asociados a las isoflavonas podían resolver ese problema.Now the inventors have found of surprising way that certain probiotic microorganisms associated with isoflavones could solve that problem.
La presente invención tiene por lo tanto por objeto unas preparaciones farmacéuticas que comprenden unos extractos titulados de isoflavonas de soja y unos microorganismos probióticos vivos, como producto de combinación para una administración simultanea, separada o extendida en el tiempo útil en el tratamiento de los síntomas asociados a la menopausia.The present invention therefore has object pharmaceutical preparations comprising some Titrated extracts of soy isoflavones and microorganisms live probiotics, as a combination product for a simultaneous administration, separated or extended in the useful time in the treatment of symptoms associated with menopause.
En un modo particular de realización, el extracto de isoflavona es titulado de 10 a 50% de isoflavonas.In a particular embodiment, the Isoflavone extract is titrated from 10 to 50% of isoflavones.
En otro modo particular de realización, los organismos probióticos son escogidos en el grupo constituido por Enterococcus faecium, Propionibacterium acidipropionici, Lactobacillus acidophilus, Lactobacilus brevis, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus rhamnosus, Pediococcus acidilactici y Streptococcus thermophilus y las mezclas de estos microorganismos.In another particular embodiment, the probiotic organisms are chosen in the group consisting of Enterococcus faecium, Propionibacterium acidipropionici, Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus rhamnosus, Pediococcus acidilactici and Streptococcus thermophilus and mixtures of these microorganisms.
En un modo particularmente ventajoso de realización de la invención, las preparaciones comprenden el extracto de isoflavonas titulado entre 10 y 50% de isoflavonas y los microorganismos probióticos son escogidos en el grupo constituido por Enterococcus faecium, Propionibacterium acidipropionici, Lactobacillus acidophilus y Lactobacilus brevis.In a particularly advantageous embodiment of the invention, the preparations comprise the isoflavone extract titrated between 10 and 50% isoflavones and the probiotic microorganisms are chosen from the group consisting of Enterococcus faecium, Propionibacterium acidipropionici, Lactobacillus acidophilus and Lactobacilus brevis .
En el sentido de la presente invención, se entiende por extracto titulado, en isoflavonas de soja, un extracto preparado como sigue: los granos de soja triturados son extraídos con una solución hidroalcohólica. Después de eliminar el alcohol, la solución acuosa es deslipidada con ayuda de un solvente orgánico y seguidamente purificada en columna sobre una resina absorbente.Within the meaning of the present invention, understood as an extract entitled, in soy isoflavones, an extract prepared as follows: crushed soybeans are extracted with a hydroalcoholic solution. After eliminating alcohol, the aqueous solution is slipped with the help of an organic solvent and then column purified on an absorbent resin.
Los organismos probióticos son escogidos basándose en sus propiedades biológicas y sus capacidades de metabolizar las isoflavonas.Probiotic organisms are chosen based on its biological properties and its capabilities of metabolize isoflavones.
Estos microorganismos pueden ser utilizados en forma de cultivos disponibles en el mercado, en forma de suspensión microbiana o preferentemente en forma de liofilizado preparado en unas condiciones clásicas conocidas por el experto en la materia.These microorganisms can be used in form of crops available in the market, in suspension form microbial or preferably in the form of lyophilisate prepared in classical conditions known to the expert in the matter.
En un modo de realización particularmente ventajoso de la invención, estos microorganismos están presentes a razón de 50.10^{9} a 1.10^{6} bacterias por dosis unitaria y el extracto de isoflavona está presente a razón de 100 a 300 mg por unidad de toma.In an embodiment particularly advantageous of the invention, these microorganisms are present at ratio of 50.10 9 to 1.10 6 bacteria per unit dose and the Isoflavone extract is present at a rate of 100 to 300 mg per socket unit
Las preparaciones, de acuerdo con la invención, son particularmente útiles como medicamento, en particular para los tratamientos de los síntomas ligados a la menopausia, en particular contra los sofocos.The preparations, according to the invention, they are particularly useful as a medicine, particularly for treatments of menopause-related symptoms, in particular Against hot flashes
Las preparaciones según la invención que
comprenden el extracto de soja y los microorganismos pueden
presentarse en cualquier de las formas seca o fluida utilizadas
habitualmente, en particular en forma de tabletas, comprimidos,
sellos, grajeas, o soluciones bebibles en asociación con cualquier
excipiente farmacéuticamente acepta-
ble.The preparations according to the invention comprising the soy extract and the microorganisms can be presented in any of the dry or fluid forms commonly used, in particular in the form of tablets, tablets, seals, grajeas, or drinkable solutions in association with any pharmaceutically acceptable excipient. -
ble.
El extracto de isoflavonas y los microorganismos probióticos pueden ser administrados también en forma de dosis unitarias separadas, en particular tabletas, comprimidos, cápsulas, sellos o unas soluciones bebibles que puedan ser administradas separadamente o simultáneamente o de manera extendida en el tiempo.Isoflavone extract and microorganisms Probiotics can also be administered as a dose separate units, in particular tablets, tablets, capsules, seals or drinkable solutions that can be administered separately or simultaneously or extensively in the weather.
Las preparaciones según la invención permiten una metabolización de las formas glicosiladas en agliconos activos desde la primera absorción, a nivel del duodeno, zona de absorción máxima del tubo digestivo.The preparations according to the invention allow a metabolization of glycosylated forms in active aglycone from the first absorption, at the level of the duodenum, absorption zone maximum of the digestive tract.
Los ejemplos que siguen ilustran la invención sin por ello limitarla.The following examples illustrate the invention without limiting it.
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Formulación 1Formulation one
- --
- extracto de soja titulado a 15% de isoflavonas, 250 mg en un sello de tamaño 1,soy extract titled at 15% of isoflavones, 250 mg in a size 1 seal,
- --
- liofilizado de Lactobacillus acidophilus, 10^{9} bacterias en un sello del tamaño 1lyophilisate of Lactobacillus acidophilus , 10 9 bacteria in a size 1 seal
tomar 1 sello de cada simultáneamente al día.take 1 seal of each simultaneously to day.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Formulación 2Formulation 2
- --
- extracto de soja titulado a 15% de isoflavonas, 100 mg,soy extract titled at 15% of isoflavones, 100 mg,
- --
- liofilizado de Lactobacillus acidophilus, 10^{9} bacterias en un sello del tamaño 1lyophilisate of Lactobacillus acidophilus , 10 9 bacteria in a size 1 seal
tomar 2 sellos de cada simultáneamente al día.take 2 stamps each simultaneously to day.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Formulación 3Formulation 3
- --
- extracto de soja titulado a 40% de isoflavonas, 200 mg formulados en un comprimido,soy extract titled at 40% of isoflavones, 200 mg formulated in one tablet,
- --
- liofilizado de Lactobacillus brevis, 10^{9} bacterias en un sello del tamaño 1lyophilisate of Lactobacillus brevis , 10 9 bacteria in a size 1 seal
tomar un sello de cada simultáneamente al día.take a stamp of each simultaneously to day.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Formulación 4Formulation 4
- --
- extracto de soja titulado a 10% de isoflavonas, 200 mg en un sello,10% soybean extract isoflavones, 200 mg in a seal,
- --
- liofilizado de Enterococcus faecium, 10^{9} bacterias en un sellolyophilisate of Enterococcus faecium , 10 9 bacteria in a seal
tomar 4 sellos de cada simultáneamente al día.take 4 stamps of each simultaneously to day.
\newpage\ newpage
Formulación 5Formulation 5
- --
- solución hidroalcohólica al 2% de extracto de soja titulado a 50% de isoflavonas, 2% hydroalcoholic solution of 50% soy extract isoflavones,
- --
- suspensión microbiana de Lactobacillus acidophilus a 10^{8} gérmenes/g,microbial suspension of Lactobacillus acidophilus at 10 8 germs / g,
tomar con ayuda de una cuchara de medida 10 ml de cada una de las soluciones cada día.take with the help of a measuring spoon 10 ml of each of the solutions every day.
Unos microorganismos, presentes en la flora fecal y capaces de metabolizar la genistina y la daidzina respectivamente en genisteina y daidzeina, han sido puestos en cultivo durante 24, 48 y 72 horas en un medio nutritivo que contiene: peptona de carne 10 g/l, extracto de carne 10 g/l, extracto de levadura 5 g/l, glucosa 20 g/l, acetato de sodio 5 g/l, tween80 1 g/l, fosfato dipotásico 2 g/l, citrato de amonio 2 g/l, sulfato de magnesio 0,2 g/l, sulfato de manganeso 0,05 g/l, y un extracto de soja. En cada una de estas etapas, se realiza una extracción de los cultivos microbianos, diluido a la mitad con metanol y seguidamente filtrado. La solución metanólica es analizada en cromatografía líquida de alta resolución. La daidzeina, genistina, daidzina y genisteina son dosificadas por cromatografía líquida de alta resolución en el extracto de partida y en los medios metabolizados por los diferentes microorganismos. Se calculan así los contenidos de las formas agliconos y glicosiladas del extracto metabolizado respecto a las formas glicosiladas (100%) en el extracto inicial.Some microorganisms, present in the flora fecal and able to metabolize genistin and daidzine respectively in genistein and daidzein, they have been put in culture for 24, 48 and 72 hours in a nutritious medium that Contains: meat peptone 10 g / l, meat extract 10 g / l, yeast extract 5 g / l, glucose 20 g / l, sodium acetate 5 g / l, tween80 1 g / l, dipotassium phosphate 2 g / l, ammonium citrate 2 g / l, 0.2 g / l magnesium sulfate, 0.05 g / l manganese sulfate, and a soy extract. In each of these stages, a extraction of microbial cultures, diluted in half with methanol and then filtered. The methanolic solution is analyzed in high performance liquid chromatography. Daidzein, genistin, daidzine and genistein are dosed by chromatography High resolution liquid in the starting extract and in the media metabolized by different microorganisms. They are calculated like this the contents of the aglycone and glycosylated forms of the extract metabolized with respect to glycosylated forms (100%) in the initial extract.
Están reunidos en la tabla 1 siguiente.They are gathered in table 1 below.
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(Tabla pasa a página siguiente)(Table goes to page next)
Estas cepas de microorganismos metabolizan aproximadamente 80% de las formas glicoconjugadas de las isoflavonas en formas agliconos que son fácilmente absorbidas en el intestino; el Enterococcus faecium, Propionibacterium acidipropionici, Lactobacillus acidophilus y Lactobacilus brevis han demostrado ser las cepas más activas.These strains of microorganisms metabolize approximately 80% of the glycoconjugated forms of isoflavones into aglycone forms that are easily absorbed in the intestine; Enterococcus faecium, Propionibacterium acidipropionici, Lactobacillus acidophilus and Lactobacilus brevis have proven to be the most active strains.
Se ha realizado con el objetivo de valorar la eficacidad de la asociación soja probiótico con el criterio de eficacia sofoco en la indicación de la menopausia con 2 grupos de mujeres menopáusicas que reciben un extracto de soja asociado o no al probiótico.It has been done with the objective of assessing the efficacy of the probiotic soy association with the criteria of suffocation efficacy in the indication of menopause with 2 groups of menopausal women who receive an associated soy extract or not to the probiotic.
Este estudio se ha desarrollado durante 3 meses con un periodo de preinclusión de un mes.This study has been developed for 3 months with a preinclusion period of one month.
Se ha tratado un grupo de 50 mujeres menopáusicas 1 vez al día con un sello que contiene 10^{9} bacterias/g de Lactobacillus acidophilus. Otro grupo de 50 mujeres menopáusicas es tratado 1 vez al día con un sello de 250 mg de extracto de soja a 15% de isoflavonas y un sello de placebo.A group of 50 menopausal women have been treated once a day with a seal containing 10 9 bacteria / g of Lactobacillus acidophilus . Another group of 50 menopausal women is treated once a day with a 250 mg seal of soy extract at 15% isoflavones and a placebo seal.
Cada sujeto ha anotado en un carnet de autoevaluación el número de sofocos diarios y su intensidad según un parámetro preestablecido.Each subject has scored on a card of self-assessment the number of daily hot flashes and their intensity according to a preset parameter.
Este estudio muestra la acción positiva importante de los probióticos en la regularidad y la intensidad de la respuesta a los fitoestrógenos, puesto que las preparaciones según la invención permiten a las mujeres que han recibido el extracto de soja asociado al probiótico constatar una disminución del número y la intensidad de los sofocos superior a las que han recibido únicamente el extracto de soja.This study shows the positive action important of probiotics in the regularity and intensity of the response to phytoestrogens, since the preparations according to the invention allow women who have received the soy extract associated with the probiotic verify a decrease of the number and intensity of hot flashes higher than those that have received only the soy extract.
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0011515A FR2813790B1 (en) | 2000-09-11 | 2000-09-11 | PHARMACEUTICAL PREPARATIONS CONTAINING SOY ISOFLAVONE EXTRACTS AND PROBIOTIC MICROORGANISMS |
| FR0011515 | 2000-09-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2267695T3 true ES2267695T3 (en) | 2007-03-16 |
Family
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| ES01402270T Expired - Lifetime ES2267695T3 (en) | 2000-09-11 | 2001-08-31 | PHARMACETUTICS PREPARATIONS CONTAINING EXTRACTS OF ISOFLAVONA SOYA AND PROBIOTIC MICROORGANISMS. |
Country Status (10)
| Country | Link |
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| US (1) | US20020114786A1 (en) |
| EP (1) | EP1186295B1 (en) |
| AT (1) | ATE333875T1 (en) |
| CA (1) | CA2356466A1 (en) |
| CY (1) | CY1106211T1 (en) |
| DE (1) | DE60121686T2 (en) |
| DK (1) | DK1186295T3 (en) |
| ES (1) | ES2267695T3 (en) |
| FR (1) | FR2813790B1 (en) |
| PT (1) | PT1186295E (en) |
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| AU2003293977A1 (en) * | 2002-10-16 | 2004-05-04 | L'oreal | Cosmetic composition for preventing and/or correcting the functional disorders of the pilo-sebaceous unit of mammals |
| EP1560503A4 (en) * | 2002-11-15 | 2006-04-05 | Cargill Inc | Soluble isoflavone compositions |
| US7025998B2 (en) * | 2003-05-30 | 2006-04-11 | Rotta Research Laboratorium S.P.A. | Phytoestrogens and probiotic for women's health |
| US7935334B2 (en) * | 2005-07-07 | 2011-05-03 | Imagilin Technologies, LLC | Probiotics as alternative medicines against infectious diseases |
| US20060093592A1 (en) * | 2004-10-04 | 2006-05-04 | Nutracea | Synbiotics |
| CA2787544C (en) | 2010-01-28 | 2019-07-09 | Ab-Biotics S.A. | Probiotic composition for use in the treatment of bowel inflammation |
| ITMI20111829A1 (en) * | 2011-10-07 | 2013-04-08 | Paladin Pharma S P A | PROCEDURE FOR THE PREPARATION OF A COMPOSITION BASED ON EQUOLO |
| KR102362968B1 (en) * | 2019-11-25 | 2022-02-17 | 주식회사 쎌바이오텍 | Composition for Preventing, Relieving or Treating Climacteric Disorders Comprising Lactic Acid Bacteria and Prebiotics |
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| JP3489930B2 (en) * | 1996-03-08 | 2004-01-26 | 株式会社ヤクルト本社 | Cancer prevention food |
| WO1998021946A1 (en) * | 1996-11-18 | 1998-05-28 | Internutria, Inc. | Composition and treatment for persistent reproductive transition symptoms |
| FI107014B (en) * | 1997-07-25 | 2001-05-31 | Oriola Oy | herbal remedies |
| DE69916414T2 (en) * | 1998-07-16 | 2005-05-19 | Aaron Tabor | SOY PREPARATIONS AND THEIR USE IN HEALTH PROMOTION |
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| CY1106211T1 (en) | 2011-06-08 |
| ATE333875T1 (en) | 2006-08-15 |
| EP1186295A1 (en) | 2002-03-13 |
| FR2813790B1 (en) | 2004-03-12 |
| FR2813790A1 (en) | 2002-03-15 |
| EP1186295B1 (en) | 2006-07-26 |
| CA2356466A1 (en) | 2002-03-11 |
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| DE60121686T2 (en) | 2007-05-03 |
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